An experimental model for hydrogen peroxide–induced tissue damage. Effects of a single inflammatory mediator on (peri)articular tissues

Abstract

Hydrogen peroxide is receiving increasing attention as a mediator of tissue damage during inflammation. To evaluate its destructive potential in vivo, we devised a model in which hydrogen peroxide is, initially, the sole mediator of tissue damage. Glucose oxidase, which was made cationic to obtain good retention in tissue, was injected intraarticularly in mouse knee joints. This enzyme produces hydrogen peroxide, using endogenous glucose as a substrate. The local production of hydrogen peroxide induced drastic vascular damage, as measured by 99mTc uptake and leakage of 125I‐albumin. The chondrocyte proteoglycan synthesis was severely inhibited, as measured by 35SO4 incorporation. Histologic examination showed impressive inflammatory and degenerative changes, including periarticular infiltration, chondrocyte death, subchondral erosions, and muscle necrosis. Intraarticular administration of catalase could inhibit these vascular effects and cartilage damage. Systemic administration of ebselen, a synthetic glutathione peroxidase‐like compound, provided partial protection. Indomethacin and piroxicam were not effective in the acute phase. We think this model is useful both for testing drugs that are purported to act as scavengers of hydrogen peroxide and for studying chronic destructive processes.

Joint inflammation and chondrocyte death become independent of Fcγ receptor type III by local overexpression of interferon‐γ during immune complex–mediated arthritis

“…H 2 O 2 is able to act on more distant targets; it easily penetrates cell membranes and has been shown to kill cells by apoptosis (40). In accordance with this, overproduction of the glycolytic enzyme glucose oxidase in the knee joint generated high levels of H 2 O 2 and caused severe chondrocyte death (41).…”

Influence of superoxide dismutase on staphylococcal arthritis—A histological and biochemical investigation using an experimental animal model

“…The reason for this rather unexpected histologic finding showing increased bacterial growth and increased damage of joints inocculated with SOD may be that: 1) SOD prevents the killing of bacteria in bacterial arthritis by removing superoxide radicals (OF), [181; 2) SOD induces increased oxygen tension, facilitating bacterial growth in vivo; 3) extensive joint damage is caused by the action of bacteria or by reactive oxygen species produced by inflammatory cells [4,18]; 4) mobilised iron may have become a strong prooxidant under our experimental conditions by injecting SOD [4,19]; 5) catalytic iron produced by destruction of bacteria or by damaged tissues and microbleeding is able to impair the phagocytic activity of PML [21]. 6) increased production of hydrogen peroxide induced by SOD causes formation of hydroxyl radicals [4,20], (Ou -+HzOz-~OH.-). At the present time it is not possible to single out which mechanisms are responsible for this apparently negative SOD effect.…”

The pharmacology of ebselen

“…In order to test whether ebselen is able to inhibit acute inflammation in which hydroperoxides are more specifically involved, paw oedema was induced in rats by the sub-plantar injection of amidated glucose oxidase (aGO), which generates H20 2 using endogeneous glucose as substrate [21]. In this model, oedema reaches a peak 2 h after injection of 10 lag aGO, neutrophil infiltration being observed histologically after 2 or 4 h, changing to mononulear infiltration by 24 h. Pretreatment with ebselen (50 mg/kg, p.o.)…”